A traditional principle in neurobiology has been that one neuron secretes only one neurotransmitter. With the recent discovery of neuropeptides, many neurons and endocrine cells have been found to synthesize and secrete more than one neurotransmitter or hormone. An important challenge in neurobiology will involve determining the presynaptic and postsynaptic regulatory processesd in multiple neurotransmitter neurons. Opiomelanotropinergic cells and neurons secrete N-acetylated and unacetylated forms of Alpha-melanocyte-stimulating hormone (Alpha-MSH), Beta-endorphin and Beta-endorphin fragments. The Beta-endorpohin actions include the induction of analgesia while Alpha-MSH appears to increase arousal, attention, learning and memory. In studies of the behavioral effects of Alpha-MSH in rats we have shown that the cognition effects are specific to learning of visual and not auditory information. It was also shown that the behavioral effects of Alpha-MSH and Beta-endorphin opposite, and that Alpha-MSH behavioral effects can be antagonized by co-administration of Beta-endorphin. It was also found that post-translational modification of Alpha-MSH and Beta-endorphin could markedly alter their neuronal actions. N-acetylation of these peptides markedly increases the behavioral potency of Alpha-MSH and markedly decreases the analgesic potency of Beta-endorphin. Because N-acetylation appeared to be a key regulatory step, the mechanism for the process was investigated. A single enzyme was identified which acetylates both Alpha-MSH and Beta-endorphin. It was also found that presynaptic cleavage of Beta-endorphin 1-31 to Beta-endorphin 1-27 eliminates the Alpha-MSH antagonistic activity of this peptide. Because of the clinical potential for Alpha-MSH in the treatment of cognitive disorders, a number of peptides were designed, synthesized and tested for behavioral potency. One peptide, Nle-4, D-Phe-7-Alpha-MSH, appeared to be an Alpha-MSH antagonist as it actually debilitated learnig in rats. In contrast, a series of cyclic-Alpha-MSH analogues were synthesized which seem to be super-potent Alpha-MSH agonists.